Field of the Invention
The present invention relates in general to a delivery system to improve administration to patients of Fenobam, its hydrates, and salts thereof. More particularly, the present invention relates to delivery systems and compositions which optimize solubility and dissolution properties and, potentially avoid hepatic first-pass metabolism. The delivery systems of the present invention can be administered as an oral vehicle for the mammalian gastrointestinal tract and take the form of tablets, capsules, pulvule, powders, liquids, suspensions, sprays, etc.
Description of Related Art
Fenobam was originally developed by McNeil Laboratories® in the late 1970's as an anxiolytic agent, but was never commercially marketed due to dose-limiting side effects (Journal of Pharmacology and Experimental Therapeutics 315(2): 711-21 & Neuropharmacology 57 (2): 97-108). This drug compound belongs to the class known as 4-oxo-2-imidazolidinylidene ureas, which was patented by McNeil Laboratories® in U.S. Pat. No. 3,983,135. Despite the age of this drug, clinical and pharmacology researchers have just recently begun exploring alternative uses for Fenobam.
Fenobam, having the formula C11H11ClN4O2, as shown in FIG. 1 below, has a molecular weight of 266.7 g/mol, and is a poorly water soluble drug compound. Equilibrium solubility data determined by applicants herein for Fenobam are shown in Table 1 below. Comparative equilibrium solubility data for Fenobam, Fenobam Monohydrate, and Fenobam Sulfate Salt are shown in Table 2 below. Further, this drug possesses a log P value of 1.863, thus indicating nominal lipophilicity.
TABLE 1Equilibrium Solubility of Fenobam by HPLCSolubilitySolvent(mg/mL)0.1 N HCl0.392Acetate Buffer, pH 4.00.025Phosphate Buffer, pH 7.40.03320% Polyethylene Glycol (PEG) 4000.124Polyethylene Glycol (PEG) 40024.420% Propylene Glycol0.065Propylene Glycol4.4610% Polysorbate 801.1910% Cremophor RH 400.64330% HP-Beta-Cyclodextrin2.19Ethanol2.90
TABLE 2Comparative Equilibrium Solubility by HPLC for Fenobam,Fenobam Monohydrate, & Fenobam SulfateSolubility mg/mLFenobamFenobam SolventFenobam (Base)MonohydrateSulfate0.1 N HCl0.3920.3080.303Phosphate0.0330.0390.027Buffer, pH 7.4PEG 40024.434.55.65
Given the solubilities shown in Tables 1 and 2 above, a traditional oral drug delivery system can neither be optimized nor deemed practical for a drug such as Fenobam, and its associated hydrates and salts. A traditional oral dosage unit typically entails powder blends, which are administered directly, or filled into capsules, or compressed into tablets. Further, these powder blends typically utilize water soluble carbohydrate based ingredients for optimizing flowability and compressibility characteristics during pharmaceutical processing. Such carbohydrate ingredients can include lactose, microcrystalline cellulose, corn starch, etc.
Since Fenobam and associated hydrate and salt forms do not demonstrate sufficient aqueous solubility, especially closer to physiological pH values, an alternate or novel oral delivery system is needed for successful drug delivery to patients. The use of microemulsions, solid dispersions, cyclodextrins, gastroretentive, and sustained delivery techniques were not in use when Fenobam was first developed by McNeil Laboratories. Hence, Fenobam solubility, dissolution, and bioavailability would not be optimal utilizing conventional oral delivery systems existing at the time Fenobam was developed, such as carbohydrate based powder blends which can be administered directly, or filled into capsules, or compressed into tablets. The use of such conventional oral delivery techniques would require much higher doses of Fenobam, thus resulting in higher adverse event profiles (i.e., dose-limiting side effects).
Fenobam is a clinically validated nonbenzodiazepine anxiolytic, and is a potent mGluR5 receptor antagonist (J Pharmacol Exp Ther. 2005 November; 315 (2): 711-21). Currently, The National Institute on Drug Abuse (Bethesda, Md.) is investigating Fenobam as a potential treatment agent for cocaine addiction. Fenobam is also being investigated for the treatment of Fragile X Syndrome (J Med Genet. 46: 266-271). With these new clinical applications for this 1970's McNeil drug, an optimal clinical dosage form is now needed using new drug delivery technologies. However, traditional oral delivery systems based on carbohydrate powder blends do not achieve optimal delivery results (i.e., solubility, dissolution, bioavailability, etc.).
Accordingly, it is an object of the present invention to provide a delivery system to improve administration to patients of Fenobam, its hydrates, and salts. More particularly, an object of the present invention is to optimize solubility and dissolution properties and, in certain instances, to potentially avoid hepatic first-pass metabolism of Fenobam, thereby enhancing bioavailability through the gastrointestinal tract.
Another object of the present invention is to provide a method and composition for enhancing solubility and dissolution of Fenobam, its hydrates, and salts by employing various novel pharmaceutical compositions described hereinafter.
Yet another object of the present invention is to provide delivery systems in which administration of Fenobam, its hydrates, and salts can take place by an oral vehicle for the mammalian gastrointestinal tract, and take the form of tablets, capsules, pulvules, powder, liquids, suspensions, and sprays.
It is still another object of the present invention to provide a delivery system to improve administration to patients of Fenobam, its hydrates, and salts, and, more particularly, to provide a delivery system involving a microemulsion, and/or solid dispersion and/or, cyclodextrin, and/or gastroretentive, and/or enteric coated, and a sustained delivery technique.
It is yet another object of the present invention to provide a drug delivery system to optimize solubility and dissolution properties of Fenobam, its hydrates, and salts, and, in certain instances, potentially avoid hepatic first-pass metabolism, thereby enhancing bioavailability through the gastrointestinal tract.
Still another object of the present invention is to provide delivery systems for Fenobam, its hydrates, and salts which can be administered as an oral vehicle for the mammalian gastrointestinal tract, and take the form of tablets, capsules, pulvules, powders, liquids, suspensions, sprays.